112 Chapter 5 INTRODUCTION Ovarian cancer is the most lethal gynecological cancer worldwide, accounting for 207,252 deaths in 2020 (1). Due to non-specific or absence of symptoms at an earlystage, patients typically present at a late-stage when prognosis is poor (2). Five-year overall survival rates sharply decrease with higher stage at diagnosis, with 92% survival in early-stage disease compared to only 29% in late-stage disease (3). High mortality rates prioritize the development of novel diagnostic approaches for ovarian cancer. Although more ovarian cancer patients were diagnosed at an earlier stage with screening strategies using conventional imaging and/or serum biomarkers (e.g. CA-125), this did not translate into reduced overall cancer-specific mortality in general and in high-risk populations (4, 5). In fact, the majority of ovarian cancers were not detected during or after the trial. A more accurate and easily accessible test could potentially overcome this problem. Testing for ovarian cancer using biomarkers related to carcinogenesis could offer such an accurate test. DNA methylation-mediated silencing of tumor suppressor genes occurs early in cancer development and is therefore promising to detect cancer at an early stage (6). Methylation analysis in urine, cervicovaginal self-samples, and cliniciantaken cervical scrapes has already been proven to allow reliable detection of cervical (7, 8) and endometrial cancer (9, 10). In urine, even signals of non-urogenital cancers, including colorectal (11) and lung cancer (12, 13), are detectable by methylation testing. The measurement of somatic mutations, aneuploidy, or DNA methylation in cliniciantaken cervical scrapes or blood demonstrated the high potential of molecular-based diagnostic tests for ovarian cancer (14-17). However, these molecular changes have not been investigated in home-collected urine and cervicovaginal self-samples of ovarian cancer patients. In this study, we explored the potential of molecular testing in home-collected urine and cervicovaginal self-samples, and clinician-taken cervical scrapes for ovarian cancer detection. Methylation markers considered suitable for the detection of ovarian cancer included a combination of markers described in studies on cervical and endometrial cancer detection in patient-friendly sample types (GALR1, GHSR, MAL, PRDM14, SST, and ZIC1 (10, 18-20)), and ovarian cancer detection in cervical scrapes and plasma (C2CD4D, CDO1, NRN1 (17, 21, 22)). In addition, the analysis of somatic copy number aberrations (SCNA) and fragmentation patterns was performed using shallow whole-genome sequencing on a subset of the samples to verify the presence of ovarian cancer-derived DNA in urine.
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